The major aim of this proposal is to investigate the roles of cytotoxic oxygen metabolites as contributors to cardiac damage which occurs during reperfusion and reoxygenation of the globally-ischemic, oxygen-deprived heart. The study uses biochemical approaches to identify which oxygen metabolites might be responsible for the damage, when they are primarily produced, and how their cytotoxic effects can be reduced or prevented by treating hearts with enzymes or other drugs which affect either their cellular production or reactivity. Every biochemical study is accompanied by selected correlative physiologic measurements of heart contractile function and coronary flow so that changes in oxygen metabolism, ischemia-reperfusion damage, and the effects of protective interventions, might be rationally related to overall organ function. Aside from identifying the fundamental biochemical component(s) of damage, another goal is to study the phenomena in the context of interventions which may have future clinical applicability for intraoperative preservation of the globally-ischemic heart. This will be done in part by evaluating agents thought to beneficially affect oxygen metabolism as supplements to hypothermic cardioplegia. Since cytotoxic oxygen metabolites are thought to play an important role in "ischemic" damage to heart, brain and gut, and are also involved in other recognized pathological states, this study's evaluation of aberrant oxygen metabolism and its pharmacological modification may have broad health-related applicability.